A growing number of serious, debilitating and often fatal diseases are associated with angiogenesis. These diseases are cumulatively called angiogenic diseases. Under normal physiological conditions, angiogenesis in mammals is endogenously controlled throughout the lifetime and neovascularization rarely occurs except during embryonic development, the reproductive cycle, and wound healing.
Examples of the pathological conditions leading to development of angiogenic diseases are, among others, arthritis, rheumatoid arthritis, atherosclerotic plaques, corneal graft neovascularization, wound healing, hypertrophic or keloid scars, proliferative retinopathy, diabetic retinopathy, macular degeneration, granulations, neovascular glaucoma and uveitis.
Additionally, rapid and excessive angiogenesis accompanies the growth of the placenta and solid tumors. Many tumors seem to produce factors which increase cell division of vascular endothelial cells and stimulate the migration and organization of endothelial cells into vessels resulting in neovascularization. In addition, factors which inhibit angiogenesis may be turned off. Activation of angiogenesis, therefore, appears to be an essential stage in tumor progression. Various mammalian endogenous molecules have been identified as angiogenic factors stimulating angiogenesis directly or indirectly. These stimulators of angiogenesis include basic fibroblast growth factor (bFGF), vascular endothelial cell growth factor (VEGF), tumor necrosis factor-α (TNF-α), and angiogenin.
The search for neovascularization inhibitors has been recently vigorously pursued. Currently, several antiangiogenic factors including thrombospondin, platelet factor-4, fumagillin, thalidomide angiostatin and endostatin are being studied. Several of these are in early clinical trials, e.g., fumagillin and thalidomide.
Since there is no effective treatment available and since angiogenic diseases present a serious medical problem there is an ongoing need for new and more efficient antiangiogenic agents.
Human hormones, such as growth hormone (hGH), prolactin (hPRL), placental lactogen (hPL) or growth hormone variant (hGH-V) are homologous protein hormones which are potent endogenous chemical substances asserting specific biological activities on their respective target organs. The biological activities of these hormones are not the same and they differ depending on the hormone and/or the hormone target organ. For example, growth hormone, which is a protein of the anterior lobe of the pituitary gland, promotes and regulates body growth and morphogenesis, fat mobilization and inhibitions of glucose utilization (Trends Endocrinol. Metab., 3:117(1992)).
Prolactin is a known hormone produced by the pituitary gland in all mammals. The normal biological function and activity of prolactin in mammals include regulation of reproduction, osmoregulation, the stimulation of milk production by the mammary gland, the modulation of steroidogenesis in the gonads, the stimulation of maternal behavior, and the modulation of immune function (Life Sci., 57:1 (1995)).
The human placenta expresses two proteins with significant structural homology to human growth hormone, namely human placental lactogen and a variant of human growth hormone, hGH-V, differing by 13 amino acid substitutions (Hormonal Proteins Peptides, 4:61 (1977)).
Human placental lactogen is somatotropic in fetal tissues and aids in stimulating mammary cell proliferation (Endocrin. Rev., 12:316 (1991)). Human growth hormone variant rather than pituitary growth hormone regulates maternal metabolism during the second half of the pregnancy (Endocrinology, 133:1292 (1993)). As described in Endocrinology, 121:2055 (1987) rodent placentas express and secrete several proteins such as proliferin and proliferin-related peptide possessing biological actions similar to prolactin rather than growth hormone.
The human placenta serves as the major respiratory, nutritional and endocrine organ throughout fetal life and is critical to the survival and healthy development of the fetus. The placenta provides an intimate interface between the maternal and fetal blood supplies. Pathological impairment of placental invasion and poor vascular development has been associated with both fetal and maternal complications.
Intrauterine fetal growth restriction (IUGR) is a condition that affects approximately 500,000 pregnancies annually in the United States. As a result of poor placental blood supply, and decreased fetal oxygenation and nutrition, this condition results in small-for-dates infants. These infants have a neonatal mortality rate 6-10 times higher than that of normal infants and are at risk for pulmonary and neurological problems at birth.
Preeclampsia, a condition that affects approximately 250,000 American pregnancies each year, puts mothers and their fetuses at high risk. Maternal hypertension, renal failure, hepatic failure, coagulopathy, cerebral edema seizures and stroke are the potential consequences of this syndrome. Fetal morbidity is 5 times higher than normal in preeclampsia.
Pathological conditions involving excessive trophoblastic invasion, such as placenta accreta and gestational trophoblastic tumors, can cause devastating maternal complications including hemorrhage and metastatic neoplasia.
All the above placental conditions associated with dysregulation of the vasculature of the developing placenta can have profound maternal and chi child health consequences.
Thus, there is a need for diagnosing and treating vascular abnormalities of the placenta. These needs and others are addressed by the instant invention.